Fragile X-associated disorders are a family of genetic conditions that may affect individuals in a variety of ways. The three fragile X-associated disorders are fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). The conditions are all caused by changes in the fragile X mental retardation 1 (FMR1) gene, located on the X chromosome. In most people, the FMR1 gene contains approximately 5-44 repeats of the cytosine guanine guanine (CGG) trinucleotide within the 5′ untranslated region.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability worldwide. FXS is characterized by an expansion to more than 200 repetitions of the CGG trinucleotide, resulting in loss or significant reduction of expression of the FMR1 gene product, fragile X mental retardation protein (FMRP).
In addition to their intellectual development disability, individuals with FXS may display associated physical features such as large ears, long face, macrocephaly, and macroorchidism. Individuals with FXS may also exhibit one or more of hyperactivity, impulsivity, multiple anxiety symptoms, repetitive/perseverative stereotypic behaviors, unstable affect, aggression, and self-injurious behavior. Males are generally more severely affected than females when carrying the mutation (heterozygous females may appear phenotypically unaffected, but may suffer reproductive abnormalities).
FXTAS is caused by a moderate expansion (55-200 repeats; premutation range) of the CGG trinucleotide in the FMR1 gene. FXTAS is an adult onset neurodegenerative disorder, e.g., occurring over 50 years of age. Affected individuals may exhibit one or more of action tremor, Parkinsonism, sensory neuropathy, cognitive dysfunction (e.g., executive impairment and dementia), anxiety, irritability, agitation, hostility, obsessive-compulsiveness, apathy, and depression.
FXPOI affects women and is also caused by a moderate expansion (55-200 repeats; premutation range) of the CGG trinucleotide in the FMR1 gene. Some women with about 44 to 54 CGG repeats may also have features of FXPOI. Affected women may exhibit intermittent and unpredictable menses, with eventual early cessation. FXPOI may also be associated with late-onset Parkinson-like neurological problems (fragile X-associated tremor ataxia syndrome, or FXTAS) including executive function deficits, tremor, ataxia, neuropathy, and brain atrophy.
In treating fragile X-associated disorders, such as FXS, it has been observed that while available agents may improve some symptoms, they aggravate others.
For instance, stimulants, such as methylphenidate and amphetamines, have been used in individuals with FXS. However, concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines. In addition, individuals with FXS treated with stimulants have reported increased anxiety, irritability, mood lability, perseveration, hyperactivity, and/or aggressive tendencies.
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline and fluoxetine, have also been used in individuals with FXS. It has been reported, however, that in some individuals, especially children, SSRIs caused behavioral activation (increase in activity level that does not include any real change in mood, impulse control, or a change in the child's demeanor or other behaviors), which can aggravate preexisting symptoms of hyperactivity and disinhibited behaviors.
Aripiprazole has also been tried in individuals with FXS. It has been reported, however, that some individuals with FXS failed treatment predominately due to aggravation of aggressive, perseverative, and irritable behavior.
Atomoxetine, a selective norepinephrine reuptake inhibitor, has also been tried in individuals with FXS. Compared to stimulants, advantages of atomoxetine may include lack of abuse potential and once-daily dosage. Six trials of atomoxetine in individuals with FXS, however, were unsuccessful, with the majority failing due to aggravation of irritable, moody, and aggressive behaviors.
Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders occur together in 25%-33% of patients. However, as discussed above, concerns about treatment with stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines. In addition, stimulants may exacerbate anxiety.
Accordingly, there remains a need for methods to treat the manifold symptoms associated with a fragile X-associated disorder such as FXS. There also remains a need for methods to treat ADHD co-morbid with anxiety.